Heretofore, macrophage migration inhibitory factor (MIF) is thought to be an exacerbation factor of various inflammatory diseases, which is released from immunocompetent cells, pituitary, etc. in rapid response to stimuli including body invasion and is located upstream of the inflammatory cytokine cascade to control inflammatory responses (Annual Reports in Medicinal Chemistry, 33, 24, 1998; Advances in Immunology, 66, 197, 1997).
MIF levels markedly increase in the synovial fluid or serum from the patient with rheumatism, in the alveolar lavage fluid from the patient with acute respiratory distress syndrome, in the urine collected during rejection from the patient who has received a kidney transplant and in the serum from the patient with acute myocardial infarction, diabetes mellitus, systemic lupus erythematosus, Crohn's disease and atopic dermatitis, as compared to healthy individuals.
It is reported that administration of an antibody against MIF and loss of MIF in various animal disease models show improving effects on symptoms of nephritis, hepatitis, pneumonia, arthritis, endotoxin shock, etc. (International Journal of Molecular Medicine, 2, 17, 1998).
In recent years, it is reported that MIF suppresses cell death induced by oxidative stress (J. Exp. Med., 190, 1375-1382, 1999 PNAS, 99, 345-350, 2001) and induces GST expression (Cardiovascular Res., 52, 438-445, 2001). 1,3-Benzothiazinone derivatives having a cell death inhibitory activity and capable of binding to MIF are reported in WO 03/20719 (Patent Document 1). It is described in WO 03/90782 that substances capable of binding to MIF (e.g., 1,3-benzothiazinone derivatives) potentiate the cell death inhibitory activity and the expression of a gene or protein production under control of antioxidant response element (ARE).
It is reported that by kinetic analysis, the Pro at the position-1 in MIF forms a hydrophobic pocket with Lys-32, Ile-64, Tyr-95 and Asn-97 to bind to various compounds (Expert Opin. Ther. Targets, 7, 153-164, 2003).
On the other hand, it has been revealed in recent years that cell death induced by oxidative stress is deeply correlated with occurring and developing of numerous disorders including neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc.), ischemic diseases (e.g., myocardial infarction, heart failure, apoplexy, cerebral infarction, ischemic acute renal failure, etc.), bone/joint diseases (e.g., osteoporosis, degenerative arthritis, rheumatism, etc.), digestive diseases (e.g., inflammatory bowel disorders, acute pancreatitis, etc.), hepatic diseases (e.g., alcoholic hepatitis, viral hepatitis, etc.), diabetes mellitus, AIDS, etc. (Extra Issue: Igaku-no-Ayumi, page 79, 2005; Extra Issue: Igaku-no-Ayumi, page 8, 1997; Nippon Rinsho, 54, 1996). The antioxidant response element (ARE) regulates the expression of a variety of protective factors against oxidative stress and its transcriptional activation is considered as one of the most important cytoprotective mechanisms against oxidative stress (Current Pharmaceutical Design, 10, 879, 2004). Furthermore, it is pointed out the possibility that overexpression of protective factors regulated by ARE would be associated with pharmaceutical effects of gold preparations and NSAIDs used for the treatment of rheumatoid arthritis (The Journal of Biological Chemistry, 276, 34074, 2001; Free Radical Biology and Medicine, 37, 650, 2002).